Circadian rhythm for tryptophan pyrrolase activity and its circulating substrate.

Hepatic tryptophan pyrrolase and its circulating substrate, whole blood tryptophan, have a circadian rhythmicity in mice. Intact adrenocortical function is required for the normal rhythmicity of both enzyme and substrate although an altered but less apparent rhythm persists in the adrenalectomized state.

Circadian periodicity of tryptophan metabolism.

Rhythmicity of tryptophan metabolism via the kynurenine pathway has been demonstrated in man. Normal subjects given 3 g of tryptophan at 0900 hours excreted almost three times the quantity of kynurenine, kynurenic acid, and xanthurenic acid than did subjects given the same dose at 2100 hours. Other metabolites of the kynurenine pathway varied in the same fashion but with lesser magnitude. In contrast, indican, a tryptophan metabolite not in the kynurenine pathway, varied inversely with the other metabolites measured. The data suggest that the liver enzyme tryptophan pyrrolase has a circadian rhythm in man similar to that already described in mice in a previous study. Tryptophan tolerance tests in the future should be controlled relative to time of amino acid administration.

Impact of infectious disease upon fat metabolism and immune functions.

Abnormalities in lipid metabolism influence immunological competence. Infectious diseases are accompanied by altered lipid metabolism as well as by suppression or stimulation of generalized defensive mechanisms and immune functions. An infectious disease may therefore introduce variables that must be recognized and evaluated during studies aimed at elucidating possible relationships between dietary lipids and the development of cancer.

Relationship between serum chromium concentrations and glucose utilization in normal and infected subjects.

Studies in healthy individuals demonstrate that serum chromium concentrations fall precipitiously following the intravenous administration of a 30-gm. glucose load. Significant decreases from baseline control fasting serum Cr concentrations were also observed when intravenous glucose was given during sandfly fever. Glucose disappearance rates also decreased significantly to approximately one half of pre-illness control values while serum Cr values declined still further. In addition, serum Cr disappearance rates could be calculated. When individual preexposure and postexposure serum glucose and Cr disappearance rates were compared, significant linear correlation was found (P smaller than 0.05). Acute infection appears to reduce the availability of circulating Cr, which may contribute to the altered glucose metabolism characteristic of acute infections even in the presence of elevated insulin levels and other hormonal changes.

A protein from polymorphonuclear leukocytes (LEM) which affects the rate of hepatic amino acid transport and synthesis of acute-phase globulins.

A proteinaceous secretion from phagocytizing polymorphonuclear leukocytes, termed "leukocytic endogenous mediator" (LEM), has been shown to have marked effects on hepatic amino acid transport and RNA and protein synthesis. A single injection of LEM results in a marked accumulation of labeled nonmetabolizable model amino acids in the liver of normal rats. The LEM-stimulated uptake of amino acids by liver was observed in adrenalectomized, hypophysectomized, thyroidectomized, or diabetic rats and could not be duplicated by pharmacological doses of a large variety of hormones. In addition, LEM stimulated an increased uptake of alpha-aminoisobutyric acid by isolated livers during their perfusion in vitro. LEM also stimulated an increased incorporation of orotic acid into hepatic RNA of intact rats, especially into the bound ribosomal fraction. This increased synthesis of RNA preceded an enhanced hepatic production of a number of the acute-phase plasma globulins. LEM did not stimulate the adenylate cyclase-cAMP system in liver and was not found to utilize this system as a second messenger. Thus, the effects of LEM in stimulating hepatic amino acid transport appear to be direct, without mediation by other hormones, and to be independent of cAMP. On the other hand, the ability of LEM to stimulate RNA and acute phase globulin synthesis in liver may require the presence of physiological quantities of hormones such as adrenal corticoids.

A probable endocrine basis for the depression of ketone bodies during infectious or inflammatory state in rats.

The effects of infection with Streptococcus pneumoniae, Francisella tularensis, and Venezuelan equine encephalitis virus as well as inflammatory stress induced by the administration of turpentine and endotoxin on plasma ketone bodies and insulin were studied in white rats. All of the infectious/inflammatory stresses caused a significant decrease in the ketonemia of fasting and an elevation of plasma insulin. When a pneumococcal infection was initiated in a diabetic rat, inhibition of fasting ketonemia did not occur. Similarly, pneumococcal infection in the hypophysectomized rat did not result in a noticeable depression of either fasting ketonemia or plasma FFA. The increase in circulating insulin appears to be closely correlated with the inhibition of fasting ketonemia noted in the infectious/inflammatory stress.

Magnitude of the host nutritional responses to infection.

This review describes the scope, complexity, and magnitude of host nutritional responses throughout the course of an infectious process. These responses include prominent changes in nitrogen and protein metabolism, altered rates of carbohydrate and lipid production and utilization, and changes in mineral, electrolyte, trace element, and vitamin metabolism. It is postulated that these responses develop in a relatively predictable sequence which is influenced by the adequacy of host antimicrobial defense mechanisms, the severity and duration of illness, and specific localization of an infectious process within the body. In addition to hormonal regulatory effects, the metabolic and nutritional responses of the host are also influenced by biologically active substances released when host cells participate in phagocytic activity and local inflammatory responses.

Herman Award Lecture, 1995: infection-induced malnutrition--from cholera to cytokines.

Infection-induced malnutrition, the most common form of cytokine-induced malnutrition, results from the actions of proinflammatory cytokines, ie, tumor necrosis factor (TNF) and interleukins 1,6, and 8 (IL-1, IL-6, and IL-8). During acute generalized infections, these cytokines initiate the acute-phase reaction. This reaction is quite stereotyped, and includes fever, malaise, myalgia, headaches, cellular hypermetabolism, and multiple endocrine and enzyme responses. In addition, there is heightened catabolism of muscle proteins and many amino acids; flux of free amino acids into the liver; hepatic synthesis of acute-phase plasma proteins; sequestration of iron and zinc; gluconeo-genesis; insulin resistance; impaired cellular uptake of fatty acids from plasma triglycerides; sizable losses of body nitrogen, potassium, magnesium, phosphate, and zinc; retention of body salt and water; heightened metabolic degradation and/or loss of vitamins; and an activation of the immune system. The pathogenesis of cytokine-induced malnutrition is thus vastly different from the malnutrition caused by uncomplicated starvation. Cytokine-induced malnutrition can have a devastating effect on the immune system and its functions. Although proinflammatory cytokines are found in mucosal fluids, where they contribute to the pathogenesis of inflammatory bowel diseases, it is not known whether cytokines play a role in toxigenic, secretory diarrheas such as cholera, which cause huge losses of body water, electrolytes, and bicarbonate while exhibiting no systemic manifestations of an acute-phase reaction.

Hypothesis: leukocyte endogenous mediator/endogenous pyrogen/lymphocyte-activating factor modulates the development of nonspecific and specific immunity and affects nutritional status.

We postulate that leukocyte endogenous mediator/endogenous pyrogen/lymphocyte-activating factor (LEM/EP/LAF) integrates the host's nonspecific and specific immune responses to infection by virtue of the panoply of physiological and metabolic activities it is capable of eliciting. The alterations in systemic metabolism modulated by LEM/EP/LAF, although apparently of value to the host in the defense against infection and the repair of tissue damage, result in negative nutrient balances. Severe infections, alone or in conjunction with injury, may result in malnutrition unless the patient is adequately nourished. Preexisting nutritional deficits can compromise host resistance to infection, in part by preventing production of LEM/EP/LAF. Additional studies of the sequelae of LEM/EP/LAF action and effects of nutrition on host resistance to infection appear warranted.

Effect of glucose infusion on the concentration of individual serum free amino acids during sandfly fever in man.

After an intravenous glucose load in man, total serum amino acid concentrations are rapidly depressed and remain below baseline values for at least 2 to 3 hr after serum glucose and insulin have returned to preload concentrations. Despite the presence of basal hypoaminoacidemia, a decreased glucose disappearance rate, and hyperinsulinemia in volunteers who were ill with sandfly fever, an intravenous glucose load resulted in a further depression of serum amino acids which was equal to or slightly greater than that observed in the same individuals before exposure to the virus. Although the infectious process may have some effect on insulin-stimulated hepatic disposal of a glucose load, it does not appear to influence the ability on insulin to decrease the rate of release of certain amino acids from skeletal muscle.

The significance and mechanism of an increased serum phenylalanine-tyrosine ratio during infection.

Infections or inflammatory states often cause significant increases in serum phenylalanine and the phenylalanine-tyrosine ratio. More than 95% of samples obtained during inflammatory diseases in man showed phenylalanine-tyrosine ratio increases greater than the maximum normal values. An increase in this ratio also occurred in monkeys with induced Rocky Mountain spotted fever, viral encephalitis, yellow fever, or pneumococcal and Salmonella infections, as well as in rats with pneumococcal and Salmonella infections, as well as in rats with pneumococcal, Salmonella or tularemia infections. A similar ratio increase occurred in rats inoculated with unpurified mediator substances (released by activated leukocytes) that appear to initiate many of the secondary metabolic phenomena associated with infection and/or inflammation. To identify responsible mechanisms, rats were given lethal doses of Streptococcus pneumoniae; serum phenylalanine and phenylalanine-tyrosine ratios increased significantly. Hepatic phenylalanine hydroxylase activities were slightly decreased when compared to noninfected controls. Infected and noninfected rats showed comparable oxidation rates for 14C-phenylalanine given with an oral phenylalanine load, as a pulse-oral dose, or as an intraperitoneal injection. After 8 hr, both infected and control rats had similar amounts of radioactivity in total body protein, but tissue distributions were markedly altered during pneumococcal sepsis. Serum proteins of infected rats contained almost twice as much total radioactivity as that found in controls, while the amount of labeled phenylalanine in skeletal muscle protein was significantly reduced in the infected group. Isolated muscles from infected rats released more phenylalanine and less tyrosine than control muscles. Infection-related increases in serum phenlalanine could not be explained by decreased hydroxylation or oxidation. Rather, the data were consistent with an increased flux of phenylalanine into serum, most likely as the result of increased skeletal muscle catabolism. Elevations in the serum phenylalanine-tyrosine ratio have potential value for estimating the presence of an inflammatory fisease and the catabolic state of a patient.

Sequential changes in body composition during infection: electron probe study IV.

Alterations occur in human muscle electrolyte and water composition in response to infection. There appear to be at least two basic mechanisms; the first is an exchange of sodium for potassium without alteration in water content of muscle. The second is an increase in cellular Na and water without a loss of K on a dry weight basis. In a series of studies in monkeys, Salmonella typhimurium sepsis was induced as an experimental model. Both patterns of muscle response to infection were detected. Electron probe microanalysis revealed that the loss of K concentration was due to an accumulation of intracellular saline which dilute the K content. The mechanism of this is unclear; however, a concomitant increase in undertermined osmoles in the serum suggests that there may be an increase in organic osmoles within the cell which leads to the dilution of intracellular K concentration.

Electrolyte metabolism in rhesus monkeys with experimental salmonella sepsis.

Prior investigations in the human indicate that alterations occur in electrolyte balance and serum concentration during infectious diseases. In order to explore these alterations in greater detail, electrolyte metabolism has been investigated in rhesus monkeys with a sublethal illness induced by intravenous inoculation with Salmonella typhimurium. The response to this illness was evaluated by a variety of measurements including serum and muscle electrolyte composition and renal function studies. In the animals with ad libitum dietary intake, a loss in muscle and serum potassium concentrations was evident within 24 h after inoculation. This was reflected in increased urinary potassium losses during the febrile phase of illness. Serum and muscle K concentrations returned to normal after 5 days of illness. Sodium and water content of muscle responded to infection in a more complex pattern. During the febrile phase, muscle sodium and water increased and sodium concentrations in serum and urine were elevated. During convalescence, renal retention of sodium was marked and overlapped the period of weight loss and the increased urine volume. This asynchrony in recovery of normal renal function appeared to be the cause of relatively large swings in plasma sodium concentrations during the early convalescent period. These investigations indicate that the altered serum concentrations in infectious diseases are the sum of renal and extrarenal factors controlling electrolyte metabolism, and that some of the most remarkable alterations occur during early convalescence as renal function returns to normal.

Future role of micronutrients on immune functions.

The future is bright in the field of micronutrients and immunity. New advances in technology now permit the design of many new research studies, and an increased application of the findings to clinical and public health practices. More investigators will need to be trained in the fundamentals of both nutritional and immunological sciences. More basic information will be needed in both fields, but the scientific and clinical values of merging these two fields are already well established. The development of additional animal models will be needed to dissect out the role of each essential micronutrient and its potential importance in each step of the immune response. Based on future studies, new RDAs must be formulated and applied widely in medical and public health practices and in public education.

Defective lipid disposal mechanisms during bacterial infection in rhesus monkeys.

Mechanisms producing hypertriglyceridemia during bacterial sepsis have not been well defined. In this study lipid disposal mechanisms were assessed in 76 infected and 19 control male rhesus monkeys by the ability to dispose of triglycerides after: (1) oral lipid loading; (2) intravenous lipid loading; and (3) by lipolytic enzyme activity tests as measured by postheparin lipolytic activity (PHLA). Studies were performed both before and 48 hr after intravenous inoculation with either Salmonella typhimurium or Diplococcus pneumoniae when illness was uniformly severe and fasting serum triglyceride elevations were increased maximally. S. typhimurium-infected monkeys demonstrated significant fasting hypertriglyceridemia (p is less than 0.001), reduced clearance of orally and intravenously administered lipid and markedly reduced PHLA. During this gram-negative sepsis, mild lethargy, slight diarrhea, and a 2% mortality were observed. During D. pneumoniae sepsis, average fasting triglyceride concentrations were slightly, but not significantly elevated. While oral lipid clearance was impaired, intravenous lipid clearance was unimpaired, and PHLA was slightly reduced. Marked lethargy, agitation, and a 20% mortality were present during this gram-positive infection. Results of this study support the concept that an impairment of lipid disposal mechanisms, particularly during gram-negative sepsis with S. typhimurium, may significantly contribute to the observed hypertriglyceridemia.

Marylanders defeat Philadelphia: yellow fever updated.

Those strategic points which influence this amateur historian to declare a victory for Baltimore and Maryland over Philadelphia are: I. Based upon clinical and epidemiological data, two Marylanders, Potter and Davidge, were among the first to contest Rush and his contagion theory; they told him so and published their views. To prove this point, Potter went to the extreme of inoculating himself with presumedly infected material. Stubbins Ffirth, a young University of Pennsylvania medical student, did the same four years later. To Rush's credit was ultimate abandonment of his originally held views. II. John Crawford, of Baltimore, although not the originator of the insect concept of transmission of infectious agents, published his concepts in 1811. III. Henry Rose Carter, a Maryland graduate, clearly delineated, in 1898, that after identification of an index case of yellow fever an extrinsic incubation period was necessary before the evolution of secondary cases. IV. James Carroll, another University of Maryland graduate, who worked as Deputy under Walter Reed with Lazear and Agramonte, helped prove Finlay's original concept that the Aedes aegypti mosquito was the natural vector of yellow fever. Carroll himself was the first experimentally induced case. V. Studies in primates provide new approaches for management of yellow fever. Nutritional support and treatment with specific anti-viral agents may be useful for therapy of human yellow fever. Maryland members of the Climatological are mindful of Philadelphia's rich medical heritage and of the many battles won in the City of Brotherly Love. Physicians in colonial and early America experienced The best and worst of times, theirs was an age of foolishness and belief, of incredulity and light, of darkness, despair and hope. This tale of two cities ends in peace.

Effects of sandfly fever on isometric muscular strength, endurance, and recovery.

The isometric muscular strength and endurance of 10 male volunteers were measured four times per day for 15 consecutive days. Eight experimental subjects were inoculated with sandfly fever virus and two double-blind controls were given sterile saline on the seventh day. The muscular performances of the control subjects remained essentially constant throughout. Decrements in muscular strength and endurance occurred with the experimentals during the brief period of illness three or four days after inoculation, then performances improved towards baseline levels.

Studies on Macaca mulatta infected with Rocky Mountain spotted fever.

Acid-base alterations and changes in other selected serum constituents (free fatty acids, triglycerides, cholesterol, copper, cortisol, alpha1-acid glycoprotein, haptoglobin, and albumin) were measured during a study of Rocky Mountain spotted fever in 16 male rhesus macaques. Blood samples were taken from nonanesthetized macaques conditioned to repeated handling. Arterial pH increased and PCO2 decreased during the febrile period. Free fatty acids, triglycerides, copper, cortisol, alpha1-acid glycoprotein, and haptoglobin increased, whereas albumin decreased during the disease. Significant changes were not observed in arterial PO2. Cholesterol remained unchanged. The increase in arterial pH and decrease in PaCO2 indicated that respiratory alkalosis was present in macaques acutely affected with Rocky Mountain spotted fever.